Antibacterial bisabolane-type sesquiterpenoids from the sponge-derived fungus Aspergillus sp

Four new bisabolane-type sesquiterpenoids, aspergiterpenoid A (1), (-)-sydonol (2), (-)-sydonic acid (3), and (-)-5-(hydroxymethyl)-2-(2',6',6'-trimethyltetrahydro-2H- pyran-2-yl)phenol (4) together with one known fungal metabolite (5) were isolated from the fermentation broth of a marine-derived fungus Aspergillus sp., which was isolated from the sponge Xestospongia testudinaria collected from the South China Sea. Four of them (1-4) are optically active compounds. Their structures and absolute configurations were elucidated by using NMR spectroscopic techniques and mass spectrometric analysis, and by comparing their optical rotations with those related known analogues. Compounds 1-5 showed selective antibacterial activity against eight bacterial strains with the MIC (minimum inhibiting concentrations) values between 1.25 and 20.0 μM. The cytotoxic, antifouling, and acetylcholinesterase inhibitory activities of these compounds were also examined.     

Steroids from the soft coral Sinularia crassa

One new sterol, crassarosterol A (1), and four new steroidal glycosides, crassarosterosides A-D (2-5) were isolated from the Formosan soft coral Sinularia crassa. The absolute configuration of 1 was determined using the Mosher's method. The absolute configurations for the sugar moieties of 2-5 were determined by HPLC analysis on the o-tolylthiocarbamates derived from the liberated sugar after acid hydrolysis. Compounds 2 and 4 could significantly inhibit the expression of pro-inflammatory iNOS protein at 10 μM. In contrast, 1-3 were found to stimulate the expression of COX-2 protein at this concentration. Steroids 1 and 4 also showed cytotoxicity toward the selected human liver cancer cells.     

Quinazolin-4-one coupled with pyrrolidin-2-iminium alkaloids from marine-derived fungus Penicillium aurantiogriseum

Three new alkaloids, including auranomides A and B (1 and 2), a new scaffold containing quinazolin-4-one substituted with a pyrrolidin-2-iminium moiety, and auranomide C (3), as well as two known metabolites auranthine (4) and aurantiomides C (5) were isolated from the marine-derived fungus Penicillium aurantiogriseum. The chemical structures of compounds 1-3 were elucidated by extensive spectroscopic methods, including IR, HRESIMS and 2D NMR spectroscopic analysis. The absolute configurations of compounds 1-3 were suggested from the perspective of a plausible biosynthesis pathway. Compounds 1-3 were subjected to antitumor and antimicrobial screening models. Auranomides A-C exhibited moderate cytotoxic activity against human tumor cells. Auranomides B was the most potent among them with an IC(50) value of 0.097 μmol/mL against HEPG2 cells.     

Cytotoxic and Anti-Inflammatory Metabolites from the Soft Coral Scleronephthya gracillimum

Five new pregnane-type steroids, sclerosteroids J–N (1–5), and a diterpenoid with a new chemotype 3-methyl-5-(10′-acetoxy-2′,6′,10′-trimethylundecyl)-2-penten-5-olide (6), have been isolated from a soft coral Scleronephthya gracillimum. The structures of the metabolites were determined by extensive spectroscopic analysis. Compound 4 exhibited cytotoxicity against HepG2, A549, and MDA-MB-231 cancer cell lines. Furthermore, steroids 2 and 4 were found to significantly inhibit the accumulation of the pro-inflammatory iNOS protein, and 1, 2, 4 and 5 could effectively reduce the accumulation of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells.     

Cytotoxic sesterterpenoids from a sponge Hippospongia sp

One new pentacyclic sesterterpene, hippospongide A (1), and one new scalarane sesterterpenoid, hippospongide B (2), along with six previously reported known scalarane-type sesterterpenes (3-8), were isolated from a sponge Hippospongia sp. The structures of these compounds were elucidated on the basis of their spectroscopic data and comparison of the NMR data with those of known analogues. These metabolites are the first pentacyclic sesterterpene and scalarane-type sesterterpenes to be reported from this genus. Compounds 3-5 exhibited significant cytotoxicity against DLD-1, HCT-116, T-47D and K562 cancer cell lines.     

Cembranoids with 3,14-ether linkage and a secocembrane with bistetrahydrofuran from the Dongsha Atoll soft coral Lobophytum sp

Four new cembranoids, lobophylins A-D (1-4), and one novel secocembrane, lobophylin E (5) were isolated from a soft coral Lobophytum sp. The structures of new metabolites were elucidated on the basis of extensive spectroscopic methods. Among these metabolites, 1-4 are rarely found cembranoids possessing a tetrahydrofuran moiety with a 3,14-ether linkage. In addition, 5 is the first secocembrane possessing two tetrahydrofuran moieties with 3,14- and 4,7-ether linkages.     

Five new amicoumacins isolated from a marine-derived bacterium Bacillus subtilis

Four novel amicoumacins, namely lipoamicoumacins A-D (1-4), and one new bacilosarcin analog (5) were isolated from culture broth of a marine-derived bacterium Bacillus subtilis, together with six known amicoumacins. Their structures were elucidated on the basis of extensive spectroscopic (2D NNR, IR, CD and MS) analysis and in comparison with data in literature.     

Simplexins P-S, eunicellin-based diterpenes from the soft coral Klyxum simplex

Four new eunicellin-based diterpenes, simplexins P-S (1-4), and the known compound simplexin A (5), have been isolated from the soft coral Klyxum simplex. The structures of the new metabolites were determined on the basis of extensive spectroscopic analysis, particularly 1D and 2D NMR experiments. Compounds 1 and 3-5 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines, 3 being the most cytotoxic.     

Secondary Metabolites from Penicillium pinophilum SD-272, a Marine Sediment-Derived Fungus

Two new secondary metabolites, namely, pinodiketopiperazine A (1) and 6,7-dihydroxy-3-methoxy-3-methylphthalide (2), along with alternariol 2,4-dimethyl ether (3) and l-5-oxoproline methyl ester (4), which were isolated from a natural source for the first time but have been previously synthesized, were characterized from the marine sediment-derived fungus Penicillium pinophilum SD-272. In addition, six known metabolites (5–10) were also identified. Their structures were elucidated by analysis of the NMR and mass spectroscopic data. The absolute configuration of compound 1 was determined by experimental and calculated ECD spectra. Compound 2 displayed potent brine shrimp (Artemia salina) lethality with LD₅₀ 11.2 μM.     

4-Methylenesterols from a Sponge Theonella swinhoei

Three new 4-methylenesterols, theonellasterol K (1), acetyltheonellasterol (2) and acetyldehydroconicasterol (3), along with two known sterols, theonellasterol (4) and theonellasterone (5), were isolated from the sponge Theonella swinhoei. The structures of these compounds were elucidated on the basis of their spectroscopic data and comparison of the NMR data with those of known analogues. Compound 1 exhibited significant cytotoxic activity against HCT-116, K562 and Molt 4 cancer cell lines.     

Bioactive (3Z,5E)-11,20-epoxybriara-3,5-dien-7,18-olide diterpenoids from the South China Sea gorgonian Dichotella gemmacea

Six new (3Z,5E)-11,20-epoxybriara-3,5-dien-7,18-olide diterpenoids, gemmacolides N-S (1-6), were isolated together with four known analogues, juncenolide D, and juncins R, S and U (7-10), from the South China Sea gorgonian Dichotella gemmacea. The structures of the new compounds were elucidated by the detailed analysis of spectroscopic data in combination with the comparison with reported data. The absolute configuration of 1 was determined by a TDDFT calculation of its solution ECD spectrum, affording the determination of absolute configuration of other analogues by simply comparing their ECD spectra with that of 1. The cytotoxic and antimicrobial activities of these compounds were evaluated. In preliminary in vitro bioassays, compounds 4, 5, 6, 8 and 9 showed cytotoxicity against A549 and MG63, while compounds 1, 2, 4, 7-10 showed antimicrobial activity against the fungus Septoria tritici and the bacterium Escherichia coli.     

Two new tryptamine derivatives, leptoclinidamide and (-)-leptoclinidamine B, from an Indonesian ascidian Leptoclinides dubius

Two new tryptamine-derived alkaloids, named as leptoclinidamide (1) and (-)-leptoclinidamine B (2), were isolated from an Indonesian ascidian Leptoclinides dubius together with C2-α-D-mannosylpyranosyl-L-tryptophan (3). The structure of 1 was assigned on the basis of spectroscopic data for 1 and its N-acetyl derivative (4). Compound 1 was an amide of tryptamine with two β-alanine units. Although the planar structure of 2 is identical to that of the known compound (+)-leptoclinidamine B (5), compound 2 was determined to be the enantiomer of 5 based on amino acid analysis using HPLC methods. Compounds 1 to 4 were evaluated for cytotoxicity against two human cancer cell lines, HCT-15 (colon) and Jurkat (T-cell lymphoma) cells, but none of the compounds showed activity.     

Bioactive eunicellin-based diterpenoids from the soft coral Cladiella krempfi

Four new eunicellin-based diterpenoids, krempfielins A-D (1-4), along with two known compounds (5 and 6) have been isolated from a soft coral Cladiella krempfi. The structures of the new metabolites were elucidated by extensive spectroscopic analysis and by comparison with spectroscopic data of related known compounds. Compounds 5 and 6 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines. Furthermore, compounds 2, 3, 5 and 6 were shown to exert significant in vitro anti-inflammatory activity against LPS-stimulated RAW264.7 macrophage cells.     

Rare Chromones from a Fungal Mutant of the Marine-Derived Penicillium purpurogenum G59

Three new and rare chromones, named epiremisporine B (2), epiremisporine B1 (3) and isoconiochaetone C (4), along with three known remisporine B (1), coniochaetone A (5) and methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (6) were isolated from a mutant from the diethyl sulfate (DES) mutagenesis of a marine-derived Penicillium purpurogenum G59. The structures of 2–4 including the absolute configurations were determined by spectroscopic methods, especially by NMR analysis and electronic circular dichroism (ECD) experiments in conjunction with calculations. The absolute configuration of the known remisporine B (1) was determined for the first time. Compounds 2 and 3 have a rare feature that has only been reported in one example so far. The compounds 1–6 were evaluated for their cytotoxicity against several human cancer cell lines. The present work explored the great potential of our previous DES mutagenesis strategy for activating silent fungal pathways, which has accelerated the discovery of new bioactive compounds.     

Lobocrassins A-E: new cembrane-type diterpenoids from the soft coral Lobophytum crassum

Five new cembrane-type diterpenoids, lobocrassins A-E (1-5), were isolated from the soft coral Lobophytum crassum. The structures of cembranes 1-5 were established by spectroscopic and chemical methods and by comparison of the spectral data with those of known cembrane analogues. Lobocrassin A (1) is the first cembranoid possessing an α-chloromethyl-α-hydroxy-γ-lactone functionality and is the first chlorinated cembranoid from soft corals belonging to the genus Lobophytum. Lobocrassins B (2) and C (3) were found to be the stereoisomers of the known cembranes, 14-deoxycrassin (6) and pseudoplexaurol (7), respectively. Lobocrassin B (2) exhibited modest cytotoxicity toward K562, CCRF-CEM, Molt4, and HepG2 tumor cells and displayed significant inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils.     

Five New Cytotoxic Metabolites from the Marine Fungus Neosartorya pseudofischeri

The marine fungus Neosartorya pseudofischeri was isolated from Acanthaster planci from the South China Sea. In a preliminary bioactivity screening, the crude methanol extract of the fungal mycelia showed significant inhibitory activity against the Sf9 cell line from the fall armyworm Spodoptera frugiperda. Five novel compounds, including 5-olefin phenylpyropene A (1), 13-dehydroxylpyripyropene A (4), deacetylsesquiterpene (7), 5-formyl-6-hydroxy-8-isopropyl-2- naphthoic acid (9) and 6,8-dihydroxy-3-((1E,3E)-penta-1,3-dien-1-yl)isochroman-1-one (10), together with eleven known compounds, phenylpyropene A (2) and C (3), pyripyropene A (5), 7-deacetylpyripyropene A (6), (1S,2R,4aR,5R,8R,8aR)-1,8a-dihydroxy-2-acetoxy-3,8-dimethyl-5- (prop-1-en-2-yl)-1,2,4a, 5,6,7,8,8a-octahydronaphthalene (8), isochaetominine C (11), trichodermamide A (12), indolyl-3-acetic acid methyl ester (13), 1-acetyl-β-carboline (14), 1,2,3,4-tetrahydro-6-hydroxyl-2-methyl-l,3,4-trioxopyrazino[l,2-a]-indole (15) and fumiquinazoline F (16), were obtained. The structures of these compounds were determined mainly by MS and NMR data. The absolute configuration of 9 was assigned by the single-crystal X-ray diffraction studies. Compounds 1–11 and 15 showed significant cytotoxicity against the Sf9 cells from S. frugiperda.     

Identification and Bioactivity of Compounds from the Fungus Penicillium sp. CYE-87 Isolated from a Marine Tunicate

In the course of our continuous interest in identifying bioactive compounds from marine microbes, we have investigated a tunicate-derived fungus, Penicillium sp. CYE-87. A new compound with the 1,4-diazepane skeleton, terretrione D (2), together with the known compounds, methyl-2-([2-(1H-indol-3-yl)ethyl]carbamoyl)acetate (1), tryptamine (3), indole-3-carbaldehyde (4), 3,6-diisobutylpyrazin-2(1H)-one (5) and terretrione C (6), were isolated from Penicillium sp. CYE-87. The structures of the isolated compounds were established by spectral analysis, including 1D (¹H, ¹³C) and 2D (COSY, multiplicity edited-HSQC and HMBC) NMR and HRESIMS, as well as comparison of their NMR data with those in the literature. The compounds were evaluated for their antimigratory activity against the human breast cancer cell line (MDA-MB-231) and their antiproliferation activity against HeLa cells. Compounds 2 and 6 showed significant antimigratory activity against MDA-MB-231, as well as antifungal activity against C. albicans.     

New Metabolites and Bioactive Actinomycins from Marine-Derived Streptomyces sp. ZZ338

An extract prepared from the culture of a marine-derived actinomycete Streptomyces sp. ZZ338 was found to have significant antimicrobial and antiproliferative activities. A chemical investigation of this active extract resulted in the isolation of three known bioactive actinomycins (1–3) and two new metabolites (4 and 5). The structures of the isolated compounds were identified as actinomycins D (1), V (2), X_0β (3), 2-acetylamino-3-hydroxyl-4-methyl-benzoic acid methyl ester (4), and N-1S-(4-methylaminophenylmethyl)-2-oxo-propyl acetamide (5) based on their nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectroscopy (HRESIMS) data as well as their optical rotation. This class of new compound 5 had never before been found from a natural resource. Three known actinomycins showed activities in inhibiting the proliferation of glioma cells and the growth of methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans and are responsible for the activity of the crude extract. Actinomycin D (1) was also found to downregulate several glioma metabolic enzymes of glycolysis, glutaminolysis, and lipogenesis, suggesting that targeting multiple tumor metabolic regulators might be a new anti-glioma mechanism of actinomycin D. This is the first report of such a possible mechanism for the class of actinomycins.     

Identification and Bioactivity of Compounds from the Mangrove Endophytic Fungus Alternaria sp.

Racemic new cyclohexenone and cyclopentenone derivatives, (±)-(4R*,5S*,6S*)-3-amino-4,5,6-trihydroxy-2-methoxy-5-methyl-2-cyclohexen-1-one (1) and (±)-(4S*,5S*)-2,4,5-trihydroxy-3-methoxy-4-methoxycarbonyl-5-methyl-2-cyclopenten-1-one (2), and two new xanthone derivatives 4-chloro-1,5-dihydroxy-3-hydroxymethyl-6-methoxycarbonyl-xanthen-9-one (3) and 2,8-dimethoxy-1,6-dimethoxycarbonyl-xanthen-9-one (4), along with one known compound, fischexanthone (5), were isolated from the culture of the mangrove endophytic fungus Alternaria sp. R6. The structures of these compounds were elucidated by analysis of their MS (Mass), one and two dimensional NMR (nuclear magnetic resonance) spectroscopic data. Compounds 1 and 2 exhibited potent ABTS [2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)] scavenging activities with EC₅₀ values of 8.19 ± 0.15 and 16.09 ± 0.01 μM, respectively. In comparison to Triadimefon, compounds 2 and 3 exhibited inhibitory activities against Fusarium graminearum with minimal inhibitory concentration (MIC) values of 215.52 and 107.14 μM, respectively, and compound 3 exhibited antifungal activity against Calletotrichum musae with MIC value of 214.29 μM.     

Alkaloids from the Mangrove-Derived Actinomycete Jishengella endophytica 161111

A new alkaloid, 2-(furan-2-yl)-6-(2S,3S,4-trihydroxybutyl)pyrazine (1), along with 12 known compounds, 2-(furan-2-yl)-5-(2S,3S,4-trihydroxybutyl)pyrazine (2), (S)-4-isobutyl-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (3), (S)-4-isopropyl-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (4), (4S)-4-(2-methylbutyl)-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (5), (S)-4-benzyl-3-oxo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbaldehyde (6), flazin (7), perlolyrine (8), 1-hydroxy-β-carboline (9), lumichrome (10), 1H-indole-3-carboxaldehyde (11), 2-hydroxy-1-(1H-indol-3-yl)ethanone (12), and 5-(methoxymethyl)-1H-pyrrole-2-carbaldehyde (13), were isolated and identified from the fermentation broth of an endophytic actinomycetes, Jishengella endophytica 161111. The new structure 1 and the absolute configurations of 2–6 were determined by spectroscopic methods, J-based configuration analysis (JBCA) method, lactone sector rule, and electronic circular dichroism (ECD) calculations. Compounds 8–11 were active against the influenza A virus subtype H1N1 with IC₅₀ and selectivity index (SI) values of 38.3(±1.2)/25.0(±3.6)/39.7(±5.6)/45.9(±2.1) μg/mL and 3.0/16.1/3.1/11.4, respectively. The IC₅₀ and SI values of positive control, ribavirin, were 23.1(±1.7) μg/mL and 32.2, respectively. The results showed that compound 9 could be a promising new hit for anti-H1N1 drugs. The absolute configurations of 2–5, ¹³C nuclear magnetic resonance (NMR) data and the specific rotations of 3–6 were also reported here for the first time.